Alternative Pharmacological Strategies for the Treatment of Alzheimer's Disease: Focus on Neuromodulator Function

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, comprising 70% of dementia diagnoses worldwide and affecting 1 in 9 people over the age of 65. However, the majority of its treatments, which predominantly target the cholinergic system, remain insufficient at reversing pathology and act simply to slow the inevitable progression of the disease. The most recent neurotransmitter-targeting drug for AD was approved in 2003, strongly suggesting that targeting neurotransmitter systems alone is unlikely to be sufficient, and that research into alternate treatment avenues is urgently required. Neuromodulators are substances released by neurons which influence neurotransmitter release and signal transmission across synapses. Neuromodulators including neuropeptides, hormones, neurotrophins, ATP and metal ions display altered function in AD, which underlies aberrant neuronal activity and pathology. However, research into how the manipulation of neuromodulators may be useful in the treatment of AD is relatively understudied. Combining neuromodulator targeting with more novel methods of drug delivery, such as the use of multi-targeted directed ligands, combinatorial drugs and encapsulated nanoparticle delivery systems, may help to overcome limitations of conventional treatments. These include difficulty crossing the blood-brain-barrier and the exertion of effects on a single target only. This review aims to highlight the ways in which neuromodulator functions are altered in AD and investigate how future therapies targeting such substances, which act upstream to classical neurotransmitter systems, may be of potential therapeutic benefit in the sustained search for more effective treatments.

Keywords: ATP; Alzheimer’s disease; hormones; metal ions; neuromodulation; neuropeptides; neurotrophins; synaptic plasticity; therapeutics.

Figure 1

Summary of neuromodulator dysfunction in Alzheimer’s disease. Alterations to neuromodulator function are being increasingly regarded as critical drivers of AD pathology and resulting neurodegeneration and cognitive deficits. Alterations to levels of neuropeptides bring about compromised neuroprotection, reduced synthesis of neurotransmitters such as acetylcholine, disrupted control of excitatory and inhibitory network balances and aberrant LTP and LTD [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. The accumulation of metal ions with Aβ exacerbates excitotoxicity and oxidative stress [45,46,47,48], and contributes to the production of toxic ROS [49,50,51,52]. Increased extracellular and reduced intracellular ATP as a result of metabolic switching [53,54] and Aβ-induced pore production in the neuronal membrane [55] underlie dysfunction of P-ATPases, [56], P2-R overactivation, excess calcium influx, mitochondrial dysfunction, abnormal mitophagy, excitotoxicity and cell death [57,58,59]. Reduced neurotrophin activation of TrK-Rs leads to increased apoptosis and LTD and reduced cell survival and LTP [60,61,62,63,64,65,66,67,68]. Activation of the p75NTR by Aβ activates GSK3β, which upregulates amyloidogenic APP processing and tau hyperphosphorylation [69,70,71,72]. Reduced levels of oestrogen and testosterone compromise synaptic integrity [73,74,75,76,77,78], whilst increased levels of FSH, LH and cortisol activate GSK3β, MAPK, PKC and PKA signalling, leading to amyloidogenic processing and tau hyperphosphorylation, oxidative stress and neuroinflammation [79,80,81,82,83,84,85,86,87].